Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat
Version of Record online: 29 JAN 2009
2008 British Pharmacological Society
British Journal of Pharmacology
Volume 155, Issue 3, pages 434–440, October 2008
How to Cite
Marcos, B., Chuang, T. T., Gil-Bea, F. J. and Ramirez, M. J. (2008), Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. British Journal of Pharmacology, 155: 434–440. doi: 10.1038/bjp.2008.281
- Issue online: 29 JAN 2009
- Version of Record online: 29 JAN 2009
- (Received May 8, 2008, Accepted June 9, 2008)
- Morris water maze;
- motor activity
Background and purpose:
The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.
The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.
Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.
Conclusions and implications:
These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.
British Journal of Pharmacology (2008) 155, 434–440; doi:10.1038/bjp.2008.281; published online 14 July 2008